Increased gestational palmitic acid predisposes offspring to congenital heart disease
Authors: Yang Lv, Ri-Feng Gao, Chen-Xi Yang, Ying-Jia Xu, Yi-Qing Yang
Journal: Cell Reports Medicine (2023)

Identification of the causes for congenital heart disease (CHD) is a prerequisite for precise prevention and personalized treatment of CHD. Zhao et al.1Zhao R. Cao L. Gu W.J. Li L. Chen Z.Z. Xiang J. Zhou Z.Y. Xu B. Zang W.D. Zhou X.Y. et al.Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.Cell Rep. Med. 2023; 4100953https://doi.org/10.1016/j.xcrm.2023.100953Abstract Full Text Full Text PDF Scopus (3) Google Scholar show increased that gestational serum palmitic acid (PA) predisposes offspring to CHD by perturbating the MARS/K-Hcy/GATA4 signaling pathway. Identification of the causes for congenital heart disease (CHD) is a prerequisite for precise prevention and personalized treatment of CHD. Zhao et al.1Zhao R. Cao L. Gu W.J. Li L. Chen Z.Z. Xiang J. Zhou Z.Y. Xu B. Zang W.D. Zhou X.Y. et al.Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.Cell Rep. Med. 2023; 4100953https://doi.org/10.1016/j.xcrm.2023.100953Abstract Full Text Full Text PDF Scopus (3) Google Scholar show increased that gestational serum palmitic acid (PA) predisposes offspring to CHD by perturbating the MARS/K-Hcy/GATA4 signaling pathway. Congenital heart disease (CHD), which refers to a wide spectrum of structural malformations occurring in the heart, valves, and endothoracic great blood vessels during embryonic cardiogenesis, represents the most prevalent kind of human birth defect, with an estimated prevalence of 1% in newborns and up to 10% in stillbirths worldwide.2Tsao C.W. Aday A.W. Almarzooq Z.I. Alonso A. Beaton A.Z. Bittencourt M.S. Boehme A.K. Buxton A.E. Carson A.P. Commodore-Mensah Y. et al.Heart Disease and Stroke Statistics - 2022 Update: A report from the American Heart Association.Circulation. 2022; 145: e153-e639https://doi.org/10.1161/CIR.0000000000001052Crossref PubMed Scopus (1611) Google Scholar,3Shi H.Y. Xie M.S. Yang C.X. Huang R.T. Xue S. Liu X.Y. Xu Y.J. Yang Y.Q. Identification of SOX18 as a new gene predisposing to congenital heart disease.Diagnostics. 2022; 12: 1917https://doi.org/10.3390/diagnostics12081917Crossref PubMed Scopus (3) Google Scholar Although tiny CHD can resolve spontaneously, severe CHD may give rise to worse health-related quality of life, reduced exercise performance, pulmonary arterial hypertension, restrictive lung dysfunction, kidney damage, impaired hepatic function, delayed neurodevelopment, brain injury, thromboembolism, infective endocarditis, congestive heart failure, cardiac arrhythmias, and sudden cardiac death.2Tsao C.W. Aday A.W. Almarzooq Z.I. Alonso A. Beaton A.Z. Bittencourt M.S. Boehme A.K. Buxton A.E. Carson A.P. Commodore-Mensah Y. et al.Heart Disease and Stroke Statistics - 2022 Update: A report from the American Heart Association.Circulation. 2022; 145: e153-e639https://doi.org/10.1161/CIR.0000000000001052Crossref PubMed Scopus (1611) Google Scholar,3Shi H.Y. Xie M.S. Yang C.X. Huang R.T. Xue S. Liu X.Y. Xu Y.J. Yang Y.Q. Identification of SOX18 as a new gene predisposing to congenital heart disease.Diagnostics. 2022; 12: 1917https://doi.org/10.3390/diagnostics12081917Crossref PubMed Scopus (3) Google Scholar Striking advance has been achieved recently in pediatric cardiovascular surgical and interventional procedures, as well as perioperative intensive care, which allows approximately 95% of children afflicted with CHD to survive into adulthood, consequently yielding an ever-increasing population of adult affected individuals reaching reproductive age, and presently, adults already outnumber children who live with CHD.3Shi H.Y. Xie M.S. Yang C.X. Huang R.T. Xue S. Liu X.Y. Xu Y.J. Yang Y.Q. Identification of SOX18 as a new gene predisposing to congenital heart disease.Diagnostics. 2022; 12: 1917https://doi.org/10.3390/diagnostics12081917Crossref PubMed Scopus (3) Google Scholar Surprisingly, the elongated average lifespan of CHD survivors is associated with a significantly increased long-term risk for morbidity and mortality, including cancer, pulmonary hypertension, renal dysfunction, thrombosis, aortopathy, heart failure, dysrhythmias, and cardiac demise.3Shi H.Y. Xie M.S. Yang C.X. Huang R.T. Xue S. Liu X.Y. Xu Y.J. Yang Y.Q. Identification of SOX18 as a new gene predisposing to congenital heart disease.Diagnostics. 2022; 12: 1917https://doi.org/10.3390/diagnostics12081917Crossref PubMed Scopus (3) Google Scholar,4Niwa K. Kaemmerer H. von Kodolitsch Y. Current diagnosis and management of late complications in adult congenital heart disease.Cardiovasc. Diagn. Ther. 2021; 11: 478-480https://doi.org/10.21037/cdt-21-165Crossref PubMed Scopus (4) Google Scholar Obviously, CHD has imposed a tremendous socioeconomic burden on human beings, underscoring the urgent need to unravel the molecular basis underpinning CHD. The four-chambered heart is the first functional organ that develops during embryogenesis, and its morphogenesis involves a complex biological process that is finely controlled in a temporal and spatial manner by an intricately coordinated network, mainly comprising transcriptional factors, signaling molecules, myocardial proteins, epigenetic modifiers, and microRNAs.4Niwa K. Kaemmerer H. von Kodolitsch Y. Current diagnosis and management of late complications in adult congenital heart disease.Cardiovasc. Diagn. Ther. 2021; 11: 478-480https://doi.org/10.21037/cdt-21-165Crossref PubMed Scopus (4) Google Scholar,5Wang G. Wang B. Yang P. Epigenetics in congenital heart disease.J. Am. Heart Assoc. 2022; 11e025163https://doi.org/10.1161/JAHA.121.025163Crossref Scopus (8) Google Scholar Increasing evidence has convincingly demonstrated that both environmental and genetic pathogenic factors can disturb cardiac developmental process, resulting in CHD.6Lee K.S. Choi Y.J. Cho J. Lee H. Lee H. Park S.J. Park J.S. Hong Y.C. Environmental and genetic risk factors of congenital anomalies: An umbrella review of systematic reviews and meta-analyses.J. Korean Med. Sci. 2021; 36: e183https://doi.org/10.3346/jkms.2021.36.e183Crossref PubMed Google Scholar,7Choudhury T.Z. Garg V. Molecular genetic mechanisms of congenital heart disease.Curr. Opin. Genet. Dev. 2022; 75101949https://doi.org/10.1016/j.gde.2022.101949Crossref PubMed Scopus (6) Google Scholar Nevertheless, to date, a definitive etiology responsible for CHD is identified in only ∼50% of affected individuals.7Choudhury T.Z. Garg V. Molecular genetic mechanisms of congenital heart disease.Curr. Opin. Genet. Dev. 2022; 75101949https://doi.org/10.1016/j.gde.2022.101949Crossref PubMed Scopus (6) Google Scholar Recently, emerging studies have substantiated the key effect of maternal metabolic disorder during pregnancy on the incidence of fetal CHD and have revealed that a high-fat diet contributes to CHD through multiple pathways.1Zhao R. Cao L. Gu W.J. Li L. Chen Z.Z. Xiang J. Zhou Z.Y. Xu B. Zang W.D. Zhou X.Y. et al.Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.Cell Rep. Med. 2023; 4100953https://doi.org/10.1016/j.xcrm.2023.100953Abstract Full Text Full Text PDF Scopus (3) Google Scholar,8Collins 2nd, R.T. Yang W. Carmichael S.L. Bolin E.H. Nembhard W.N. Shaw G.M. National Birth Defects Prevention StudyMaternal dietary fat intake and the risk of congenital heart defects in offspring.Pediatr. Res. 2020; 88: 804-809https://doi.org/10.1038/s41390-020-0813-xCrossref PubMed Scopus (5) Google Scholar,9Mires S. Reddy S. Skerritt C. Caputo M. Eastwood K. Maternal metabolomic profiling and congenital heart disease risk in offspring: A systematic review of observational studies.Prenat. Diagn. 2023; https://doi.org/10.1002/pd.6301Crossref PubMed Scopus (1) Google Scholar In the current study, Zhao et al.1Zhao R. Cao L. Gu W.J. Li L. Chen Z.Z. Xiang J. Zhou Z.Y. Xu B. Zang W.D. Zhou X.Y. et al.Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease.Cell Rep. Med. 2023; 4100953https://doi.org/10.1016/j.xcrm.2023.100953Abstract Full Text Full Text PDF Scopus (3) Google Scholar demonstrated via clinical analysis and in vitro and in vivo investigations in mouse models that increased maternal serum palmitic acid (PA) levels led to CHD by post-translational modification of GATA4, unveiling a new potential molecular target for prenatal prophylaxis of CHD. The authors conducted gas chromatography coupled with either a flame ionization detector or a mass spectrometer of serum samples from pregnant women to explore the association of different types of free fatty acids (FFAs) and total FFA levels with fetal CHD. They analyzed the serum samples from 32 pregnant women bearing children with CHD and 16 pregnant women with healthy fetuses and found that the serum FFAs and total FFA levels of pregnant women with CHD fetuses were significantly elevated. Statistical analysis showed that maternal PA and total FFA levels were strongly related to the risk of CHD in fetuses. Based on these findings, they established a mouse model with a high-PA diet. Compared with mice with normal diet, the incidence of CHD in the offspring of pregnant mice with a high-PA diet increased significantly (2.97% versus 31.96%). The western blot experiments confirmed that the expressions of methionyl-tRNA synthetase (MARS) and lysine homocysteinylation (K-Hcy) in mouse embryos fed with a high-PA diet were significantly increased, and the expression of K-Hcy could be inhibited by supplementing N-acetyl-L-cysteine (NAC). However, the level of homocysteine did not change significantly, and the level of K-Hcy protein could not be reduced by folic acid supplementation, which implied that PA promoted the expression of MARS and increased the level of K-Hcy through ways other than folic acid. In addition, the JASPAR database was used to predict the potential transcription factors binding to the MASR promoter region and confirmed that PA activated the NF-κB pathway, which increased the binding between RELA and the MARS promoter region and upregulated the expression of MARS. In addition to the discovery of novel links between PA and MARS, the authors also explored how activated K-Hcy signals promoted the development of CHD. The authors screened CHD-related transcription factors according to the CHD characteristics of the individuals and the affected offspring of pregnant mice and observed the interaction between GATA4 and MARS. It was found that MARS-induced K-Hcy modification occurred at lysine 300 residue of GATA4 (K300), which inactivated GATA4 and blocked its binding to the downstream target gene promoter and increased the expression levels of endothelial/endocardial transcription factors, providing an explanation for PA-induced CHD. In contrast, the researcher established a Mars knockout mouse model, and the ablation of Mars successfully reduced the incidence of CHD in the offspring of pregnant rats fed by PA. In summary, this study indicates that increased maternal serum PA during pregnancy upregulates the MARS expression through activating the NF-κB pathway and increases the K-Hcy modification of GATA4, which predispose the offspring to CHD (Figure 1). The posttranscriptional regulatory mechanism explains the molecular pathogenesis of PA-associated CHD, suggesting a novel preventive strategy for fetal CHD in pregnant women with high circulating PA. Future work needs to expand the specific roles of different K-Hcy-modified proteins in the cardiac organogenesis and occurrence of CHD. The authors declare no competing interests. Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart diseaseZhao et al.Cell Reports MedicineFebruary 20, 2023In BriefZhao et al. report that elevated maternal serum palmitic acid (PA) is associated with the risk of congenital heart disease (CHD) in offspring. PA induces CHD phenotypes in mice via promoting K-Hcy of GATA4, therefore inhibiting its transcriptional activity. Inhibition of K-Hcy rescued PA-induced CHD occurrence. Full-Text PDF Open Access